This implementation study sought to determine what works to support brief smoking cessation (BSC) in acute hospital settings, through exploration of organizational delivery and the role of healthcare professionals (HCPs). We used a realist approach, with embedded stakeholder engagement, within a large health organization. We conducted interviews (n = 27), a survey (n = 279) and organization documentation review (n = 44). The final programme theory suggests HCPs implement BSC when they value it as part of their role in contributing to improved patient outcomes; this is due to personal and professional influences, such as knowledge or experience. Organizational support, training and working in an environment where BSC is visible as standard care, positively influences implementation. However, the context exerts a strong influence on whether BSC is implemented, or not. HCPs make nuanced judgements on whether to implement BSC based on their assessment of the patient’s responses, the patient’s condition and other acute care demands. HCPs are less likely to implement BSC in dynamic and uncertain environments, as they are concerned about adversely impacting on the clinician–patient relationship and prioritize other acute care requirements. Organizations should actively promote BSC as a core function of the acute hospital setting and improve professional practice through leadership, training, feedback and visible indicators of organizational commitment. HCPs can be persuaded that implementing BSC is an acute care priority and an expectation of standard practice for improving patient outcomes.